PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes.
Publication/Presentation Date
4-1-2018
Abstract
INTRODUCTION: Combined immune checkpoint blockade has led to rare autoimmune complications, such as fatal myocarditis. Recent approvals of several anti-programmed death 1 (anti-PD-1) drugs for lung cancer treatment prompted ongoing clinical trials that directly combine PD-1 inhibitors with thoracic radiotherapy for locally advanced lung cancer. Overlapping toxicities from either modality have the potential to increase the risk for radiation-induced cardiotoxicity (RICT), which is well documented among patients with Hodgkin's disease and breast cancer.
METHODS: To investigate cardiotoxicity without the compounding pulmonary toxicity from thoracic radiotherapy, we developed a technique to deliver cardiac irradiation (CIR) in a mouse model concurrently with PD-1 blockade to determine the presence of cardiac toxicity by using physiological testing and mortality as end points along with histological analysis.
RESULTS: We observed an acute mortality of 30% within 2 weeks after CIR plus anti-PD-1 antibody compared with 0% from CIR plus immunoglobulin G (p = 0.023). Physiological testing demonstrated a reduced left ventricular ejection fraction (p < 0.01) by echocardiogram. Tissue analyses revealed increased immune cell infiltrates within cardiac tissue. Depletion of CD8-positive lymphocytes with anti-CD8 antibody reversed the acute mortality, suggesting that the toxicity is CD8-positive cell-mediated. To validate these findings using a clinically relevant fractionated radiotherapy regimen, we repeated the study by delivering five daily fractions of 6 Gy. Similar mortality, cardiac dysfunction, and histological changes were observed in mice receiving fractionated radiotherapy with concurrent anti-PD-1 therapy.
CONCLUSIONS: This study provides strong preclinical evidence that radiation-induced cardiotoxicity is modulated by the PD-1 axis and that PD-1 blockade should be administered with careful radiotherapy planning with an effort of reducing cardiac dose.
Volume
13
Issue
4
First Page
510
Last Page
520
ISSN
1556-1380
Published In/Presented At
Du, S., Zhou, L., Alexander, G. S., Park, K., Yang, L., Wang, N., Zaorsky, N. G., Ma, X., Wang, Y., Dicker, A. P., & Lu, B. (2018). PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 13(4), 510–520. https://doi.org/10.1016/j.jtho.2017.12.002
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
29247829
Department(s)
Administration and Leadership
Document Type
Article